The most precise, powerful and safest disease prevention and treatment mechanism known is the natural ‘sterilizing’ immune response which combines elements of both innate and adaptive immunity to clear the body of a large variety of foreign pathogens without medical intervention. The immune system is designed to ‘remember’ the cleared foreign antigens in order to quickly mount an immune response upon re-infection. Immune systems, even those of cancer patients, can recognize and mount a response to foreign antigens, such as found on viruses and bacteria, sufficiently enough to completely destroy and eliminate them from the body. The ferocity and specificity of this sterilizing immune response can be witnessed in the manner in which an inadequately suppressed immune system can completely destroy large transplanted organs, such as a kidney, liver or heart, while sparing self tissues. The destructive effect of this immunity against foreign antigens would be beneficial if this effect could be redirected to tumors and/or other antigens that escape due to an insufficient immune response by the patient.
Immunotherapy is dedicated to developing methods to harness, direct and control the immune response against a variety of infectious and noninfectious diseases including cancer. Therapeutic vaccines are a type of immunotherapy designed to educate the immune system. In patients with existing cancers, the vaccines are designed so the patient's immune system recognizes the tumor cells as foreign. If tumors are recognized by the immune system as a foreign pathogen, an immune response could theoretically be elicited which could cause immune cells to destroy large tumors and seek out and destroy metastatic tumor cells wherever they reside in the body. After successful immunotherapy, the ability of the immune system to ‘remember’ eliminated foreign cells would enable the immune system to eliminate any recurrent cancer cells without any additional treatment, much like the immune system protects against opportunistic infections.
An individual's immune system response to diseases or to disease organisms can be either a Th1 response or Th2 response. In a Th1 response, the CD4+ T cells become polarized toward Th1 cells and conversely, in a Th2 response, the CD4+ T cells become polarized toward Th2 cells. This increasingly popular classification method is referred to as the Th1/Th2 balance. Th1 cells promote cell-mediated immunity, while Th2 cells induce humoral immunity. Cellular immunity (Th1) directs natural killer cells (NK), T-cells and macrophages to attack abnormal cells and microorganisms at sites of infection. Humoral immunity (Th2) results in the production of antibodies used to neutralize foreign invaders. In general, Th2 polarization of CD4+ T cells has been shown to relate to cancer progression in most human and animal cancer studies, while Th1 polarization is correlated with tumor regression and anti-tumor immunity.
The immune response of an individual, Th1/Th2 balance, can be evaluated through the balance of cytokines in the individual. Cytokines are small cell-signaling protein molecules. The term cytokine is used as a generic name for a diverse group of soluble proteins and peptides that act as regulators normally at nano- to picomolar concentrations and which, either under normal or pathological conditions, modulate the functional activities of individual cells and tissues. These proteins also mediate interactions between cells directly and regulate processes taking place in the extracellular environment. Interleukins are a group of cytokines involved in immunomodulation and can be synthesized by a variety of cells in the immune system. There are a number of interleukins, such as IL-2, IL-4, IL-10 and IL-12, and each of these interleukins has a specific role within the immune system.
Th1 cells produce Type 1 cytokines that are involved in inflammatory responses. Type 1 cytokines include, for example, IL-2, IL-12, IL-15, IFN-gamma, TNF-alpha, TNF-beta, GM-CSF and C-C chemokines. Th2 cells produce Type 2 cytokines that are involved in humoral immune responses. Type 2 cytokines include, for example, IL-4, IL-5, IL-6, IL-10, IL-13 and TGF-beta. Th1 and Th2 immune responses are counter-regulatory, such that increased Type 1 responses downregulate Type 2 responses and increased Type 2 responses downregulate Type 1 responses.
IL-12 is a heterodimer composed of a p35 and a p40 subunit. It is produced primarily by Antigen Presenting Cells (APC). IL-12 can also be produced by monocytes and macrophages, dendritic cells and B-cells. IL-12 exerts immunomodulatory effects on T-cells and natural killer cells. Endogenous IL-12 is known to be involved in generating optimal Th1 responses and can play an important role in cell-mediated immunity against intracellular pathogens.
IL-12 has been the subject of intense investigation because it modulates important components of the immune system and has been demonstrated to have dramatic anti-tumor effects in the laboratory and in animal studies. IL-12 has been implicated, for example, in inhibiting growth of human lung adenocarcinoma and acute myeloid leukemia. However, the use of exogenous IL-12 in a therapeutic regimen has been limited by high toxicity in humans.